N-but-3-enyl norbuprenorphine and its use as analgesic

ABSTRACT

The present invention provides compound having the structure: and pharmaceutically acceptable salts or derivatives thereof, as well as compositions including such compounds. The invention also provides methods of (1) preventing pain, (2) treating pain, (3) inducing sedation, (4) treating opiate addiction, (5) treating opiate withdrawal (abstinence syndrome) and/or (6) treating cough in a patient in need thereof by administering a compound or composition of the invention.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application Ser.No. 60/272,819, filed Mar. 2, 2001, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a compound that has significantselectivity for μ opioid receptors versus δ, κ, and ORL-1 receptors;compositions and unit dosage forms of the compound; and methods of usingsuch compound, compositions, and unit dosage forms.

BACKGROUND OF THE INVENTION

The opioid system modulates several physiological processes includinganalgesia, stress responses, immune responses, respiration, andneuroendocrine function (Herz, Opioids 1993, Vol. 1, Springer-Verlag,Berlin). Pharmacological and molecular cloning studies have identifiedfour opioid receptor types (mu, delta, kappa, and ORL-1) that mediatethese diverse effects (Miotto et al., The Pharmacology of OpioidPeptides (Ed. L. Tseng) 1995, 57-71, Harwood Acad. Publishers; Kiefferet al., Cell Mol. Neurobiol. 1995, 15:615-35). The opioid receptors areknown to couple with pertussis toxin sensitive G-proteins to modulateadenylyl cyclase activity and potassium and calcium channel currents(Handbook of Experimental Pharmacology, Vol.104/I:Opioids I (Herz, A;Ed.) 1993, Springer-Verlag, Berlin; Duggan and North, Pharm. Rev. 1983,35:219-282).

Most clinically used opiates are mu (μ) receptor ligands. For example,β-endorphins and enkephalins are endogenous ligands for the μ receptor.Dynorphin A also has high affinity for μ receptors, but has a higheraffinity for kappa (κ) receptors (see below). Morphine and othermorphine-like agonists produce analgesia primarily through interactionwith μ receptors. Other physiological effects that are associated with μreceptor activation include, but are not limited to, respiratorydepression, miosis, reduced gastrointestinal motility, and euphoria(Parternak, Clin. Neuropharmacol 1993, 16:1-18). In situ hybridizationstudies have shown that μ receptor mRNA is present in brain regionsassociated with pain perception (e.g., periaqueductal gray, spinaltrigeminal nucleus, cunate and gracile nuclei, and thalamus),respiration (e.g., nucleus of the solitary tract, nucleus ambiguus, andparabrachial nucleus), and nausea and vomiting (e.g., neurons of thearea postrema) (The Pharmacological Basis of Therapeutics, 9^(th)edition (Eds Hardman, J G and Limbird, L E) 1996 McGraw-Hill, N.Y.). Itis hypothesized that addiction to morphine and analgesics occurs throughhyperactivation of μ receptors.

Subclasses of the κ receptor have been identified. In situ hybridizationstudies show that the κ₁ receptor subtype is predominantly present inhypothalamic regions, which accounts for receptor effects onneuroendocrine systems. Spinal activation of the κ₁ receptor subtypeelicits analgesia in animal models. κ₃ receptor activation is alsoassociated with analgesia, however it has been shown to produce itseffects through supraspinal mechanisms (Clark, et al., J. Pharmacol.Exp. Ther. 1989, 251:461-468; Paul, et al., J. Pharmacol. Exp. Ther.1991, 257:1-7). The κ₂ receptor subtype was identified based on bindingstudies, but the pharmacological effects of this receptor are currentlyunknown. Selective κ receptor ligands can induce analgesia that isundiminished by μ receptor tolerance. These ligands produce a majorityof the observed pharmacological and physiological effects in the spinalcord and produce less intense respiratory depression than μ agonists. κreceptor agonists also produce neuroendocrine effects and dysphoric,psychomimetic effects (Pheiffer, A. et al., Science 1986, 233:744-746).

Two subclasses of the delta (δ) receptor have been identified, δ₁and δ₂,based primarily on differential sensitivity to antagonists. Activationof these receptors produces analgesic effects through spinal andsupraspinal mechanisms, although the spinal mechanism appears to be morerobust. Activation of these receptors also produces positive reinforcingeffects at supraspinal sites and antinociception for thermal stimuli atspinal sites (Pasternak, Clin. Neuropharmacol, 1993, 16:1-18). In situhybridization studies have shown that the δ receptor is localized in thedorsal horn of the spinal cord.

A number of studies have demonstrated a broad spectrum of physiologicalfunctions of the ORL-1 receptor in both the central and peripheralnervous systems and in non-neuronal tissues. These functions includemodulation of nociception (Meunier et al, Nature 1995, 377:532-5;Reinscheid et al., Science 1995, 270:792-794; Tian, et al., Br JPharmacol 1998, 124:21-6), locomotor activity (Reinscheid et al.,Science 1995, 270:792-794), reversal of stress-induced analgesia (Mogil,et al., Neuroscience 1996, 75:333-7), attenuation of stress responses(Jenck, et al., Proc Natl Acad Sci USA 1997, 94:14854-8), modulation oflearning and memory (Mamiya, et al., Brain Res. 1998, 783:236-40;Manabe, et al., Nature 1998, 394:577-81; Sandin, et al., Eur J Neurosci1997, 9:194-7), regulation of neurotransmitter and hormone release(Bryant, et al., Brain Res 1998, 807:228-33; Murphy, et al.,Neuroscience 1996, 75:1-4), modulation of kidney function (Kapusta, etal., Life Sci 1997, 60:L15-21), and a potential role in neuronaldifferentiation (Buzas, et al., J Neurochem 1999, 72:1882-9; Saito, etal., Biochem Biophys Res Commun 1995, 217:539-45; Saito, et al., J BioChem 1996, 271:15615-22).

There is a continuing need in the art to develop ligands that are highlyselective for one opioid receptor versus another. Development of suchligands will allow for further understanding of the pharmacology ofthese receptors. Additionally, such selective ligands may representnovel drugs for the treatment of pain, cough, and/or addiction thatminimize adverse effects due to interaction with other opioid receptors.

SUMMARY OF THE INVENTION

The present invention contemplates a compound (I) having the structure:

and a pharmaceutically acceptable salt, ether derivative, esterderivative, acid derivative, enantiomer, diastereomer, racemate,polymorph, or solvate thereof.

The present invention also contemplates a composition comprising acompound with the structure of formula (I) or salts or derivativesthereof.

The present invention contemplates a composition comprising a compoundwith the structure of formula (I) or a salt or derivative thereof, andfurther comprising: an adjuvant; an anti-oxidant; a buffer; a carrier; acolorant; a diluent; a disintegrant; an excipient; a filler; aflavorant; a gelling agent; a lubricant; a neutralizing agent; apreservative; or any combination of any of the foregoing.

The present invention contemplates a composition comprising (a) acompound with the structure of formula (I) or a salt or derivativethereof, and further comprising (b) an adjuvant; an anti-oxidant; abuffer; a carrier; a colorant; a diluent; a disintegrant; an excipient;a filler; a flavorant; a gelling agent; a lubricant; a neutralizingagent; a preservative; or any combination of any of the foregoing,wherein the compound is present in an opioid receptor agonizingeffective amount.

The present invention contemplates a composition comprising (a) acompound with the structure of formula (I) or a salt or derivativethereof, and further comprising (b) an adjuvant; an anti-oxidant; abuffer; a carrier; a colorant; a diluent; a disintegrant; an excipient;a filler; a flavorant; a gelling agent; a lubricant; a neutralizingagent; a preservative; or any combination of any of the foregoing;wherein the compound is present in a μ opioid receptor agonizingeffective amount.

The present invention contemplates a composition comprising (1) ananalgesic effective amount, (2) a sedative effective amount, (3) anopiate addiction treatment effective amount, (4) an opiatewithdrawal-relieving effective amount and/or (5) an anti-tussiveeffective amount of a compound with the structure of formula (I) or asalt or derivative thereof, and further comprising: an adjuvant; ananti-oxidant; a buffer; a carrier; a colorant; a diluent; adisintegrant; an excipient; a filler; a flavorant; a gelling agent; alubricant; a neutralizing agent; a preservative; or any combination ofany of the foregoing.

The present invention contemplates a composition comprising (1) ananalgesic effective amount, (2) a sedative effective amount, (3) anopiate addiction treatment effective amount, (4) an opiatewithdrawal-relieving effective amount and/or (5) an anti-tussiveeffective amount of a compound with the structure of formula (I) or asalt or derivative thereof, and further comprising: an adjuvant; ananti-oxidant; a buffer; a carrier; a colorant; a diluent; adisintegrant; an excipient; a filler; a flavorant; a gelling agent; alubricant; a neutralizing agent; a preservative; or any combination ofany of the foregoing; wherein the compound is from about 0.1 mg to about1000 mg. Alternatively, the compound is provided in the composition insuch as way as to achieve a maximum blood plasma concentration of about20 pg/ml to about 10 ng/ml.

The present invention also contemplates a unit dosage form comprising acomposition comprising a compound with the structure of formula (I) or asalt or derivative thereof.

The present invention also contemplates a unit dosage form comprising acomposition comprising a compound with the structure of formula (I) or asalt or derivative thereof, wherein the unit dosage form is selectedfrom the group consisting of tablets, pills, capsules, boluses, powders,granules, sterile parenteral solutions, sterile parenteral suspensions,elixirs, tinctures, metered aerosol, liquid sprays, drops, ampoules,autoinjector devices, suppositories, transdermal patches, and alyophilized composition.

The present invention also contemplates a unit dosage form comprising acomposition comprising a compound with the structure of formula (I) or asalt or derivative thereof, where the unit dosage form is a sustainedrelease dosage unit form.

The present invention contemplates a method of stimulating μ opiatereceptors in a patient in need thereof, the method comprisingadministering a μ opiate receptor agonizing effective amount of acomposition comprising a compound with the structure of formula (I) or asalt or derivative thereof to the patient.

The present invention also contemplates a method of stimulating μ opiatereceptors in a patient in need thereof, the method comprisingadministering a μ opiate receptor agonizing effective amount of acomposition comprising a compound with the structure of formula (I) or asalt or derivative thereof to the patient, where the administration isselected from the group consisting of oral, intravenous, intramuscular,subcutaneous, transdermal, pulmonary, ophthalmic, transmucosal, andbuccal administration.

The present invention also contemplates a method of (1) preventing pain,(2) treating pain, (3) inducing sedation, (4) treating opiate addiction,(5) treating opiate withdrawal (abstinence syndrome) and/or (6) treatingcough in a patient in need thereof, the method comprising administeringan effective amount of a composition comprising a compound with thestructure of formula (I) or a salt or derivative thereof to the patient.

The present invention also contemplates a method of (1) preventing pain,(2) treating pain, (3) inducing sedation, (4) treating opiate addiction,(5) treating opiate withdrawal (abstinence syndrome) and/or (6) treatingcough in a patient in need thereof, the method comprising administeringan effective amount of a composition comprising a compound with thestructure of formula (I) or a salt or derivative thereof to the patient,where the administration is selected from the group consisting of oral,intravenous, intramuscular, subcutaneous, transdermal, pulmonary,ophthalmic, transmucosal, epidural, intrathecal, and buccaladministration.

The present invention contemplates a method of treating pain in apatient in need thereof, the method comprising administering ananalgesic effective amount of a composition comprising a compound withthe structure of formula (I) or a salt or derivative thereof to thepatient, wherein the pain is moderate or severe.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound that has selectivity for μopioid receptors as compared to δ, κ, and ORL-1 receptors; compositionsand unit dosage forms of the compound; and methods of using suchcompound, compositions, and unit dosage forms. The compound,N-but-3-enyl-norbuprenorphine, has the structure:

Without wishing to be bound by any particular theory,N-But-3-enyl-norbuprenorphine (I) has been found to be a partial agonistof the μ, δ, κ, and ORL-1 opioid receptors. A partial agonist is anagent that binds to, but does not fully stimulate, the receptor. Inaddition, the agent prevents the binding of a full agonist, therebyblocking the total pharmacologic activity possible from the receptor.

Certain preferred embodiments of the present invention are describedbelow. In so far as the description refers to certain components of theinvention with approximations, e.g., the terms “about” or“approximately”, these terms shall generally mean an acceptable degreeof error for the quantity measured given the nature or precision of themeasurements. Typical, exemplary degrees of error are within 20 percent(%), preferably within 10%, and more preferably within 5% of a givenvalue or range of values. Alternatively, and particularly in biologicalsystems, the terms “about” and “approximately” may mean values that arewithin an order of magnitude, preferably within 5-fold and morepreferably within 2-fold of a given value. Numerical quantities givenherein are approximate unless stated otherwise, meaning that the term“about” or “approximately” can be inferred when not expressly stated.

Salts and Derivatives

Various pharmaceutically acceptable salts, ether derivatives, esterderivatives, acid derivatives, and aqueous solubility alteringderivatives of the compound also are encompassed by the presentinvention. The present invention further includes all individualenantiomers, diastereomers, racemates, and other isomer ratios of thecompound. The invention also includes all polymorphs and solvates, suchas hydrates and those formed with organic solvents, of this compound.Such isomers, polymorphs, and solvates may be prepared by methods knownin the art, such as by regiospecific and/or enantioselective synthesisand resolution, based on the disclosure provided herein. In so far asthe application contemplates ether derivatives of formula (I), suchderivatives may include C1 -C6 lower alkyl or alkenyl, branched orunbranched ethers, optimally substituted by one or more heteroatoms,such as N, O, S, Si, or halogen-substituted lower (C1 -C6) alkyl groups.With respect to ester derivatives of formula (I), such derivatives mayinclude C1-C6 lower alkyl, branched or unbranched esters.

Suitable salts of the compound include, but are not limited to, acidaddition salts, such as those made with hydrochloric, hydrobromic,hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic,glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicyclic, p-aminosalicylic,2-phenoxybenzoic, and 2-acetoxybenzoic acid; salts made with saccharin;alkali metal salts, such as sodium and potassium salts; alkaline earthmetal salts, such as calcium and magnesium salts; and salts formed withorganic or inorganic ligands, such as quaternary ammonium salts.

Additional suitable salts include, but are not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate,citrate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,triethiodide and valerate salts of the compound of the presentinvention.

The present invention includes prodrugs of the compound of the presentinvention. Prodrugs include, but are not limited to, functionalderivatives of the compounds of the present invention which are readilyconvertible in vivo into the compound of the present invention, such asaxetil and pivoxetil. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

In the context of this application, when reference is made to thecompound of the invention, such a reference shall also include salts orderivatives of the compound of the invention.

Synthesis

The compound of the present invention may be prepared by anyconventional methods known in the art. In one example,α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxyα-methyl, (αS,5α,7α)-6,14-ethenomorphinan-7-methanol (norbuprenorphine)(0.2 g, 0.47 mmole; available from Tasmanian Alkaloids (Tasmania),McFarlan Smith (U.K.); alternatively, norbuprenorphine can be preparedfrom buprenorphine using the scheme proposed by Duyang et al., TripReport: 222^(nd) American Chemical Society National Meeting, Chicago,Ill., Aug. 26-30 (2001), which can be found athttp://www.albmolecular.com/features/tekreps/vol26/no58) may be reactedwith a halo-alkene/alkane in the presence of a base and a solvent. Thereaction can be conducted at a temperature of about 0° C. to aboutreflux temperatures for about 5 to about 48 hours. The ratio ofnorbuprenorphine to alkene/alkane may be from about 1:1 to about 1:10,with a ratio of 1:1 being preferred. In a preferred embodiment, thenorbuprenorphine is reacted with 4bromo-1-butene in DMF and sodiumbicarbonate. In a further embodiment, the reaction is conducted at 95°C. for 16 hours.

The reaction mixture is then cooled and concentrated to dryness underreduced pressure, and the residue is taken up in a non-polar solvent,and washed with water. An example of a non-polar solvent that may beused is, but is not limited to, methylene chloride. The resultingorganic layer is dried (Na₂SO₄) and concentrated under reduced pressure.This material can be purified by any method known in the art. In apreferred embodiment, the product is purified by flash chromatography onsilica gel (2% methanol in methylene chloride).

Pharmaceutical Compositions

The compound, salt, derivative and/or prodrug of the present inventionmay be formulated into a pharmaceutical composition. The pharmaceuticalcomposition also may include additives, such as a pharmaceuticallyacceptable carrier, a flavorant, a sweetener, a preservative, a dye, abinder, a suspending agent, a dispersing agent, a colorant, adisintegrant, an excipient, a diluent, a lubricant, a plasticizer, anedible oil or any combination of any of the foregoing.

Suitable pharmaceutically acceptable carriers include, but are notlimited to, ethanol, water, glycerol, aloe vera gel, allantoin,glycerin, vitamin A and E oils, mineral oil, PPG2 myristyl propionate,vegetable oils and solketal.

Suitable binders include, but are not limited to, starch, gelatin,natural sugars, such as glucose, sucrose and lactose, corn sweeteners,natural and synthetic gums, such as acacia, tragacanth, vegetable gum,and sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like.

Suitable disintegrants include, but are not limited to, starch, such ascorn starch, or methyl cellulose, agar, bentonite, xanthan gum and thelike.

Suitable lubricants include, but are not limited to, sodium oleate,sodium stearate, magnesium stearate, sodium acetate, and the like.

The composition may also include suitable preservatives, e.g., sodiumbenzoate, and other additives the may render the composition moresuitable for ingestion and or injection, e.g., sodium chloride, whichaffects the osmolarity of the preparation.

A suitable suspending agent is, but is not limited to, bentoite.

Suitable dispersing and suspending agents include, but are not limitedto, synthetic and natural gums, such as vegetable gum, tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone and gelatin.

Suitable edible oils include, but are not limited to, cottonseed oil,corn oil, palm oil, sesame oil, coconut oil and peanut oil.

A suitable pharmaceutical diluent is, but is not limited to, water,saline, or lactated Ringer's solution.

Examples of additional additives include, but are not limited to,sorbitol, talc, stearic acid, and dicalcium phosphate.

Unit Dosage Fonts

The pharmaceutical compositions may be formulated as unit dosage forms,such as tablets, pills, capsules, boluses, powders, granules, sterileparenteral solutions, sterile parenteral suspensions, sterile parenteralemulsions, elixirs, tinctures, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories. Unit dosage forms maybe used for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation,transdermal patches, and a lyophilized composition.

Solid unit dosage forms may be prepared by mixing the compound, salt orderivative of the present invention with a pharmaceutically acceptablecarrier and any other desired additives as described above. The mixtureis typically mixed until a homogeneous mixture of the compound of thepresent invention and the carrier and any other desired additives areformed, ie., until the compound is dispersed evenly throughout thecomposition.

Tablets or pills can be coated or otherwise compounded to form a unitdosage form which has delayed and/or prolonged action, such as timerelease and sustained release unit dosage forms. For example, the tabletor pill can comprise an inner dosage and an outer dosage component, thelatter being in the form of an envelope over the former. The twocomponents can be separated by an enteric layer which serves to resistdisintegration in the stomach and permits the inner component to passintact into the duodenum or to be delayed in release.

Biodegradable polymers for controlling the release of the compound,include, but are not limited to, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydro-pyrans, polyanhydrides, polycyanoacrylates, cross-linked oramphipathic block copolymers of hydrogels, cellulosic polymers, andpolyacrylates.

Liquid unit dosage forms include, but are not limited to, aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavored emulsions with edible oils, as well as elixirs and similarpharmaceutical vehicles. These dosage forms may be prepared bydissolving or suspending the compound of the present invention in theliquid carrier.

Topical preparations typically contain a suspending agent andoptionally, an antifoaming agent. Such topical preparations may beliquid drenches, alcoholic solutions, topical cleansers, cleansingcreams, skin gels, skin lotions, and shampoos in cream or gelformulations (including, but not limited to aqueous solutions andsuspensions).

Administration

The pharmaceutical composition or unit dosage forms of the presentinvention may be administered by a variety of routes such asintraveneous, intratracheal, subcutaneous, oral, parenteral, buccal,sublingual, opthalmic, pulmonary, transmucosal, transdermal, andintramuscular. Unit dosage forms also can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches known to those ofordinary skill in the art.

Pharmaceutical compositions and unit dosage forms of the presentinvention for administration parenterally, and in particular byinjection, typically include a pharmaceutically acceptable carrier, asdescribed above. A preferred liquid carrier for depot forms is vegetableoil. Injection may be, for example, intravenous, epidural, intrathecal,intramuscular, intraruminal, intratracheal, or subcutaneous for purposesof depot delivery and sustained effect.

The compound, pharmaceutical compositions, or unit dosage forms of thepresent invention also can be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compound of the present invention also may be delivered by the useof monoclonal antibodies as individual carriers to which the compoundmolecules are coupled.

The compound of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers include, but are notlimited to, polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacryl-amidephenol,polyhydroxy-ethylaspartamidephenol, and polyethyl-eneoxideopolylysinesubstituted with palmitoyl residues.

A transdermal dosage form also is contemplated by the present invention.Transdermal forms may be a diffusion-driven transdermal system(transdermal patch) using either a fluid reservoir or a drug-in-adhesivematrix system. Other transdermal dosage forms include, but are notlimited to, topical gels, lotions, ointments, transmucosal systems anddevices, and iontophoretic (electrical diffusion) delivery system.Transdermal dosage forms may be used for timed release and sustainedrelease of the compound of the present invention.

The pharmaceutical compositions or unit dosage forms of the presentinvention may be administered to an animal, preferably a human being, inneed thereof to agonize and/or antagonize activity of the μ receptors.The pharmaceutical composition may be used to treat various conditions,such as pain, cough, opiate withdrawal (abstinence syndrome) and/or drugaddiction. The compound, pharmaceutical composition, or unit dosage formof the present invention may be administered alone at appropriatedosages defined by routine testing in order to obtain optimalinteraction with the μ receptor or its activity while minimizing anypotential toxicity.

The daily dosage of the compound of the present invention may varyaccording to a variety of factors such as underlying disease states, theindividual's condition, weight, sex and age and the mode ofadministration. For oral administration, the pharmaceutical compositionscan be provided in the form of scored or unscored solid unit dosageforms containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0,or 50.0 milligrams of the compound, salt or derivative of the presentinvention for the symptomatic adjustment of the dosage to the patient tobe treated. An effective amount of the compound, salt or derivative maybe supplied at a dosage level of from about 0.01 mg/kg to about 100mg/kg of body weight per day. In a preferred embodiment, the effectiveamount of the compound, salt or derivative of the invention isadministered by any appropriate method to achieve a blood concentrationof from 20 pg/ml to 10 ng/ml.

In a preferred embodiment, an “analgesic effective amount” of thecompound, salt or derivative of the invention is administered to thepatient in need of analgesic treatment. An “analgesic effective amount”is that amount of the compound that reduces or alleviates pain in thepatient, as determined by the degree of pain suffered by the patient,together with such factors as the height, weight, age, and condition ofthe patient, as well as the route of administration of the compound.

Alternatively, a “receptor agonizing effective amount” of the compoundis administered to the patient in need thereof. Such an amount is thatamount of the compound which binds to and stimulates receptor function.

The present invention also provides methods employing a “sedatingeffective amount” of the compound, salt or derivative of the invention.Such an amount is that amount that exerts a soothing or tranquilizingeffect on the patient. A sedative may be general, local, nervous orvascular.

The compound, salt or derivative of the invention may be administered inan “antitussive effective amount,” which is that amount of the compound,salt or derivative that reduces or relieves coughing in a patient, asdetermined by the height, weight, age, and condition of the patient, aswell as the route of administration of the compound.

Finally, the compound, salt or derivative of the invention may also beadministered in an “addiction-relieving effective amount” which is thatamount of the compound, salt or derivative that reduces the desire ofthe patient for opiates.

Alternatively, the compound, salt or derivative of the invention may beadministered in an “opioid withdrawal-relieving effective amount” whichis that amount of the compound, salt or derivative that reduces thesymptoms of abstinence syndrome in the patient.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.Optimal precision in achieving concentrations of drug within the rangethat yields efficacy without toxicity requires a regimen based on thekinetics of the drug's availability to target sites. This involves aconsideration of the absorption, distribution, metabolism, and excretionof a drug.

The pharmaceutical composition or unit dosage form may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. In addition,co-administration or sequential administration of other active agentsmay be desirable. For combination treatment with more than one activeagent, where the active agents are in separate dosage formulations, theactive agents can be administered concurrently, or they each can beadministered at separately staggered times. The dosage amount may beadjusted when combined with other active agents as described above toachieve desired effects. On the other hand, unit dosage forms of thesevarious active agents may be independently optimized and combined toachieve a synergistic result wherein the pathology is reduced more thanit would be if either active agent were used alone.

Generally, topical preparations contain from about 0.01% to about 100%by weight of the compound, salt or derivative, based upon 100% totalweight of the topical preparation. In a preferred embodiment, topicalpreparations contain from about 0.1% to about 50% by weight of thecompound, salt or derivative, and more preferably from about 1.0% toabout 25% by weight of the compound, salt or derivative.

Generally, the pharmaceutical composition for parenteral administrationcontains from about 0.01% to about 90% by weight of the compound, saltor derivative of the present invention, based upon 100% weight of totalpharmaceutical composition. In a preferred embodiment, preparations forparenteral administration contain from about 0.1% to about 50% by weightof the compound, salt or derivative, and more preferably from about 1.0%to about 25% by weight of the compound, salt or derivative.

Generally, transdermal dosage forms contain from about 0.01% to about100% by weight of the compound, salt or derivative, based upon 100%total weight of the dosage. In a preferred embodiment, transdermalpreparations contain from about 0.1% to about 50% by weight of thecompound, salt or derivative, and more preferably from about 1.0% toabout 25% by weight of the compound, salt or derivative.

Finally, the preparations or compositions of the present invention maycontain the compound, salt or derivative as about 50% or more by weightof the active ingredient, preferably, about 75% or more, morepreferably, 90% or more, 95% or more, 99% or more, 99.5% or more, ormost preferably 99.9% or more by weight of active ingredient.

The present invention also contemplates kits comprising a compound orcomposition of the invention. In a preferred embodiment, such a kitcontains a suitable container for the components of the kit, which mayinclude, without limitation, an effective amount of the compound, saltor derivative or composition of the invention, tailored according to itsintended use, as described above, as well as a label for the kit, andprinted instructions for use of the compound or composition of theinvention which are once again, tailored according to the intended useof the kit, such as, e.g., to treat or prevent pain, to induce sedation,to treat opiate addiction or withdrawal, and/or to treat cough.

EXAMPLES Example 1 Synthesis of N-But-3-Enyl, Norbuprenorphine

To a suspension ofα-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6methoxy-α-methyl,(αS,5α, 7α)-6,14-ethenomorphinan-7-methanol (norbuprenorphine) (0.2 g,0.47 mmole; available from Tasmanian Alkaloids (Tasmania)) in 2 mL ofDMF was added sodium bicarbonate (0.146 g, 1.74 mmole) and4-bromo-1-butene (0.064 g, 0.47 mmole). The reaction mixture was stirredat 95° C. for 16 hours. The cooled reaction mixture was concentrated todryness under reduced pressure, and the residue was taken up in 10 mlmethylene chloride and washed 3×10 mL with water. The resulting organiclayer was dried (Na₂SO4) and concentrated under reduced pressure toyields a pale brown oil, which crystallized upon standing. This materialwas purified by flash chromatography on silica gel (2% methanol inmethylene chloride) to yield 0.1 gram of the desired product as anoff-white crystalline solid. FAB High Resolution Mass Spectrum m/z468.3091 [M+1]⁺, calculated 468.3114.

Example 2 Receptor Binding Studies

Delta₂ Binding Assay: The receptor source was a human recombinant cellline. The radioligand used in the studies was [³H]-naltrindole. Bindingreactions were conducted in 50 mM Tris-HCl (pH=7.4) containing 5 mMMgCl₂ at 25° C. for 60 minutes. The binding reactions were terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity trappedonto the filters was determined and compared to control values.

Kappa Binding Assay: The receptor source was a human recombinant cellline. The radioligand used in the studies was [³H]-diprenorphine.Binding reactions were conducted in 50 mM Tris-HCl (pH=7.4) containing10 mM MgCl₂ and 1 mM EDTA at 25° C. for 60 minutes. The bindingreactions were terminated by rapid vacuum filtration onto glass fiberfilters. Radioactivity trapped onto the filters was determined andcompared to control values.

Mu Binding Assay: The receptor source was a human recombinant cell line.The radioligand used in the studies was [³H]-diprenorphine. Bindingreactions were conducted in 50 mM Tris-HCl (pH=7.4) containing 10 mMMgCl₂ at 25° C. for 60 minutes. The binding reactions were terminated byrapid vacuum filtration onto glass fiber filters. Radioactivity trappedonto the filters was determined and compared to control values.

ORI-1 Binding Assay: The receptor source was a human recombinant cellline. The radioligand used in the studies was [³H]-nociceptin. Bindingreactions were conducted in 25 mM HEPES buffer (pH=7.4) containing 10 mMMgCl2 and 1 mM EDTA at 25° C. for 60 minutes. The binding reactions wereterminated by rapid vacuum filtration onto glass fiber filters.Radioactivity trapped onto the filters was determined and compared tocontrol values.

Ki values were determined using the Cheng-Pruss of equation. Results ofthe binding studies with various ligands are shown in Table 1.

TABLE 1 Ki values (nM) Compound Delta Kappa Mu ORL-1 Buprenorophine 1.90.157 1.33 218 Norbuprenorphine 856 31 1.36 1190 Buprenorphine N-oxide16 14.8 3.11 31.3 N-But-3-enylnorbuprenorphine 113 15.4 0.224 2800

The binding data for N-but-3-enylnorbuprenorphine indicate highestaffinity for mu, relatively high affinity for kappa, modest affinity fordelta and low affinity for orphanin. Noteworthy is the activity for thiscompound at the mu receptor—it is six times more active thanbuprenorphine. Its activities at delta, kappa and orphanin receptors areless than buprenorphine by 60-fold, 100-fold and 20-fold, respectively.

Example 3 Opioid Receptor Binding and Functional Profile forN-(3′-Butenyl)-Norbupren Rphine; Activity at the Mu, Kappa, Delta andORE-1 Receptors

This in-vitro pharmacological study was initiated to assess the bindingand functional properties of buprenorphine and its analog,N-(3′-Butenyl)-norbuprenorphine. The butenyl buprenorphine derivative,compared to buprenorphine, has an equally high affinity for the mureceptor and decreased affinity at the kappa, delta and ORL-1 receptors.Functional profiling of the N-(3-Butenyl)-norbuprenorphine compound hasresulted in a rank order potency of mu >kappa≅delta>ORL-1. This compoundis a partial agonist at all four opioid receptors, with the highestefficacy at the delta receptor.

A. Mu Opioid Receptor Binding

Radioligand dose-displacement assays used 0.2 nM [³H]-diprenorphine(Perkin Elmer, Boston, Mass.; 50.0 Ci/mmole) with 20 μg membrane protein(recombinant mu opioid receptor expressed in CHO-K1 cells; Perkin Elmer)in a final volume of 500 μl binding buffer (10 mM MgCl₂, 1 mM EDTA, 5%DMSO, 50 mM Trizma base, pH 7.4). Unlabeled naloxone (Sigma) served asthe assay positive control (concentration range 3×10⁻⁷ to 1×10⁻¹³ M).All reactions were performed in 96-deep well polypropylene plates for 2h at room temperature. Binding reactions were terminated by rapidfiltration onto 96-well Unifilter GF/C filter plates (Packard, Meriden,Conn.) presoaked in 0.5% polyethylenimine (Sigma). Harvesting wasperformed using a 96-well tissue harvester (Brandel) followed by threefiltration washes with 500 μl ice-cold binding buffer. Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty μl/wellscintillation cocktail (BetaScint; Perkin Elmer) was added and plateswere counted in a Packard Top-Count for 1 min/well.

B. Kappa Opioid Receptor Binding

Radioligand dose-displacement assays used 0.40 nM [³H]-U69,593 (PerkinElmer; 41.4 Ci/mmole) with 20 μg membrane protein (recombinant kappaopioid receptor expressed in HEK 293 cells; Perkin Elmer) in a finalvolume of 500 μl binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4).Unlabeled naloxone (Sigma) served as the assay positive control(concentration range 3×10⁻⁶ to 3×10⁻¹³ M). All reactions were performedin 96-well polypropylene plates for 1 h at room temperature. Bindingreactions were terminated by rapid filtration onto 96-well UnifilterGF/C filter plates (Packard) presoaked in 0.5% polyethylenimine (Sigma).Harvesting was performed using a 96-well tissue harvester (Brandel)followed by five filtration washes with 500 μl ice-cold binding buffer.Filter plates were subsequently dried at 50° C. for 2-3 hours. Fiftyμl/well scintillation cocktail (BetaScint; Perkin Elmer) was added andplates were counted in a Packard Top-Count for 1 min/well.

C. Delta Opioid Receptor Binding

Radioligand dose-displacement assays used 0.2 nM [³H]-Naltrindole(Perkin Elmer; 33.0 Ci/mmole) with 12.5 μg membrane protein (recombinantdelta opioid receptor expressed in CHO-K1 cells; Perkin Elmer) in afinal volume of 200 μl binding buffer (5 mM MgCl₂, 5% DMSO, 50 mM Trizmabase, pH 7.4). Unlabeled naloxone (Sigma) served as the assay positivecontrol (concentration range 1×10⁻⁵ to 1×10⁻¹² M). All reactions wereperformed in 96-well polypropylene plates for 1 h at room temperature.Binding reactions were terminated by rapid filtration onto 96-wellUnifilter GF/C filter plates (Packard) presoaked in 0.5%polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Brandel) followed by five filtration washes with 200μl ice-cold binding buffer. Filter plates were subsequently dried at 50°C. for 2-3 hours. Fifty μl/well scintillation cocktail (BetaScint;Perkin Elmer) was added and plates were counted in a Packard Top-Countfor 1 min/well.

D. ORL-1 Opioid Receptor Binding

Membranes were prepared from recombinant HEK-293 cells expressing thehuman opioid receptor-like receptor (ORL-1) (Perkin Elmer) were preparedby lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000× g for 15 min at 4° C. and pellets resuspended in hypotonicbuffer to a final concentration of 1-3 mg/ml. Protein concentrationswere determined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

Radioligand binding assays used 0.1 nM [3H]-nociceptin (Perkin Elmer;87.7 Ci/mmole) with 20 μg membrane protein in a final volume of 500 μlbinding buffer (10 mM MgC12, 1 mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4).Unlabeled nociceptin (Sigma) served as the assay positive control(concentration range 2×10−7 to 6×10−13 M). All reactions were performedin 96-deep well polypropylene plates for 2 h at room temperature.Binding reactions were terminated by rapid filtration onto 96-wellUnifilter GF/C filter plates (Packard) presoaked in 0.5%polyethylenimine (Sigma). Harvesting was performed using a 96-welltissue harvester (Brandel) followed by three filtration washes with 500μl ice-cold binding buffer. Filter plates were subsequently dried at 50°C. for 2-3 hours. Fifty μl/well scintillation cocktail (BetaScint;Wallac) was added and plates were counted in a Packard Top-Count for 1min/well.

E. Opioid Receptor [³⁵S]GTPγS Binding Functional Assays

Functional [³⁵S]GTPγS binding assays were conducted by sequentiallymixing the following reagents in the order shown to yield the indicatedfinal concentrations; (0.066 μg/μl ORL-1, 0.026 μg/μl Mu, 0.020 μg/μlKappa or 0.012 μg/μl Delta) membrane protein, 10 μg/ml saponin, 3 μM GDPand 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl/well)was transferred to 96-shallow well polypropylene plates containing 10 μlof 20× concentrated stock solutions of compound or appropriate controlprepared in DMSO. Unlabeled DAMGO, U-69,593, Met-Enkephalin, andNociceptin (all from Sigma) served as the assay positive controls forthe mu, kappa, delta and ORL-1 functional assays respectively. Plateswere incubated for 30 min at room temperature with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GFAB filterplates (Packard) using a 96-well tissue harvester (Brandel) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH7.4). Filter plates were subsequently dried at50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (BetaScint;Wallac) was added and plates were counted in a Packard Top-Count for 1min/well.

Data from both binding and functional assays were analyzed using thecurve fitting functions in GraphPad PRISM™, v. 3.0. Data were expressedas mean ±S.E.M.

F. Opioid Receptor Binding Results

(i) Mu Opioid Receptor Binding Results

Buprenorphine and its butenyl derivative were equipotent in this assaywith K_(i) values of 0.30 and 0.38 nM respectively. The mu opioidreceptor binding summary is outlined in Table 2.

(ii) Kappa Opioid Receptor Binding Results

The naloxone assay control for this assay gave an expected average Kivalue of 3.7 nM The Ki value for buprenorphine was 0.036 nM which isapproximately 10 times more potent than the butenyl derivative whichgave a Ki value of 0.34 nM. The kappa opioid receptor binding summary isoutlined in Table 2.

(iii) Delta Opioid Receptor Binding Results

The naloxone control performed within the expected range. The bindingaffinities for buprenorphine and the butenyl buprenorphine were 6.5 and365 nM respectively. The delta opioid receptor binding summary isoutlined in Table 2.

(iv) ORL-1 Opioid Receptor Binding Results

The nociceptin assay control gave a typical Ki value of 0.30 nM. Thebinding affinities for buprenorphine and its derivative were 40 and 1025nM respectively. The ORL-1 opioid receptor binding summary is outlinedin Table 2.

TABLE 2 In-Vitro Binding Profile Binding K_(i) Values (nM) Compound MuK_(i) Kappa K_(i) Delta K_(i) ORL-1 K_(i) Naloxone Control 1.2 ± 0.2 3.7± 0.9 625 ± 168 nd Nociceptin Control nd nd nd 0.30 ± 0.01 Buprenorphine0.30 ± 0.14 0.036 ± 6.6 ± 1.4 40 ± 8  0.006 N-(3′-Butenyl)- 0.38 ± 0.12 0.34 ± 365 ± 134 1025 ± 214  norbuprenorphine 0.05

(v) Opioid Receptor [³⁵S]GTIγS Binding Functional Assay Results

The butenyl derivative did not display as high potency to the receptorsin the functional assay as buprenorphine. However, the butenylderivative was slightly more efficacious at the mu, kappa and ORL-1receptors. None of the efficacy values exceeded 50%. The mu, kappa,delta and ORL-1 opioid receptor functional summaries are outlined inTable 3.

TABLE 3 In-Vitro Functional Profile Functional GTPgS Activity (nM) MuKappa Delta ORL-1 Efficacy Efficacy Efficacy Efficacy Compound EC₅₀ %DAMGO EC₅₀ % U-69,593 EC₅₀ % Met-Enk EC₅₀ % Noci DAMGO Control 130 ± 11 100 ± 0%  nd nd nd Nociceptin nd nd nd 0.60 ± 0.21 100 + 0%  ControlU-69,593 nd 37 ± 9  100 ± 0%  nd nd Control Met-Enkephalin nd nd 9.3 ±2.2 100 ± 0%  Control Buprenorphine 0.45 ± 0.08 12 ± 1% 0.56 ± 0.17 11 ±0% 3.3 ± 0.3 12 ± 1% 325 ± 123 36 ± 3% N-(3′-Butenyl)- 3.0 ± 0.9 28 ± 4%19 ± 4  16 ± 1% 32 ± 9  47 ± 0% 448 ± 49  19 ± 2% norbuprenorphine

TABLE 4 In-Vitro Pharmacological Profile Functional Functional GTPgSFunctional GTPgS Functional GTPgS GTPgS Activity Activity (nM) Activity(nM) Activity (nM) (nM) Mu Kappa Delta ORL-1 Binding K₁ Values (nM)Efficacy Efficacy Efficacy Efficacy Compound Mu K₁ Kappa K₁ Delta K₁ORL-1 K₁ EC₅₀ % DAMGO EC₅₀ % U-69,593 EC₅₀ % Met-Enk EC₅₀ % NociNaloxone 1.2 ± 3.7 ± 625 ± nd nd nd nd nd Control 0.2 0.9 168 DAMGO ndnd nd nd 130 ± 100 ± nd nd nd Control 11 0% Nociceptin nd nd nd 0.30 ±nd nd nd 0.60 ± 100 + Control 0.01 0.21 0% U-69,593 nd nd nd nd nd 37 ±100 ± nd nd Control 9 0% Met- nd nd nd nd nd nd 9.3 ± 100 ± ndEnkephalin 2.2 0% Control Buprenorphine 0.30 ± 0.036 ± 6.6 ± 40 ± 0.45 ±12 ± 0.56 ± 11 ± 3.3 ± 12 ± 325 ± 36 ± 0.14 0.006 1.4 8 0.08 1% 0.17 0%0.3 1% 123 3% N-(3′-Butenyl)- 0.38 ± 0.34 ± 365 ± 1025 ± 3.0 ± 28 ± 19 ±16 ± 32 ± 47 ± 448 ± 19 ± norbu- 0.12 0.05 134 214 0.9 4% 4 1% 9 0% 492% prenorphine

These experiments show that the N-(3′-Butenyl)-norbuprenorphine bindsthe same receptors as the buprenorphine control. This butenyl compoundcompared to buprenorphine has a lower binding affinity for all of thereceptors except for mu where they are equipotent. Buprenorphinedisplays the highest affinity for the kappa receptor, followed by mu,delta and ORL-1, whereas, the butenyl derivative binds the mu and kappareceptor equipotently, followed by delta then ORL-1.

Functionally, buprenorphine and the butenyl compound have agonisteffects at the receptors in the same rank order of potency(mu>kappa>delta>ORL-1). While the two compounds are equipotent at theORL-1 receptor, buprenorphine is 6-, 31- and 11-fold more potent at themu, kappa and delta receptors, respectively. The higher buprenorphinepotency is not reflected in the efficacy rank order. The butenylderivative is slightly more efficacious at the mu, kappa and deltareceptors. It is the most efficacious at the delta receptor (47%). Bothcompounds act as partial agonists with none of the efficacies exceeding50% of control.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and anyaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Patents, patent applications, publications, procedures, and the like arecited throughout this application, the disclosures of which areincorporated herein by reference in their entireties.

1. A compound having the structure:

pharmaceutically acceptable salt, aqueous, enantiomer, diastereomer,racemate, polymorph, or solvate thereof.
 2. A composition comprising acompound as defined in claim
 1. 3. A composition as defined in claim 2,further comprising: (a) an adjuvant; (b) an anti-oxidant; (c) a buffer;(d) a carrier; (e) a colorant; (f) a diluent; (g) a disintegrant; (h) anexcipient; (i) a filler; (j) a flavorant; (k) a gelling agent; (l)alubricant; (m) a neutralizing agent; (n) a preservative; or (o) anycombination of any of the foregoing.
 4. A composition as defined inclaim 3, comprising an opiate receptor agonizing effective amount ofsaid compound.
 5. A composition as defined in claim 4, wherein saidopiate receptor is a μ receptor.
 6. A composition as defined in claim 3,comprising an analgesic effective amount of said compound.
 7. Acomposition as defined in claim 3, comprising a sedative effectiveamount of said compound.
 8. A composition as defined in claim 3,comprising an anti-tussive amount of said compound.
 9. A composition asdefined in claim 3, comprising an opioid withdrawal-relieving effectiveamount of said compound.
 10. A composition as defined in claim 3,comprising an opioid addiction-relieving effective amount of saidcompound.
 11. A composition as defined in claim 1, comprising 50% ormore by weight of said compound.
 12. A composition as defined in claim1, comprising 90% or more by weight of said compound.
 13. A compositionas defined in claim 1, comprising 99.9% or more by weight of saidcompound.
 14. A composition as defined in claim 3, comprising saidcompound in an amount sufficient to achieve a maximum bloodconcentration of from about 20 pg/ml to about 10 ng/ml of said compound.15. A unit dosage form comprising a composition as defined in claim 2.16. A unit dosage form as defined in claim 15, selected from the groupconsisting of tablets, pills, capsules, boluses, powders, granules,sterile parenteral solutions, sterile parenteral suspensions, elixirs,tinctures, metered aerosol, liquid sprays, drops, ampoules, autoinjectordevices, suppositories, transdermal patches, and a lyophilizedcomposition.
 17. A unit dosage form as defined in claim 15, which is asustained release unit dosage form.
 18. A unit dosage form as defined inclaim 15, comprising 50% or more by weight of said compound.
 19. A unitdosage form as defined in claim 15, comprising 90% or more by weight ofsaid compound.
 20. A unit dosage form as defined in claim 15, comprising99.9% or more by weight of said compound.